1. The General Linear Model (GLM) SPM Course 2010 University of Zurich, 17-19 February 2010 Klaas Enno Stephan Laboratory for Social & Neural Systems Research Institute for Empirical Research in Economics University of Zurich Functional Imaging Laboratory (FIL) Wellcome Trust Centre for Neuroimaging University College London With many thanks for slides & images to: FIL Methods group

2. Overview of SPM RealignmentSmoothing Normalisation General linear model Statistical parametric map (SPM) Image time-series Parameter estimates Design matrix Template Kernel Gaussian field theory p <0.05 Statisticalinference

3. Passive word listening versus rest 7 cycles of rest and listening Blocks of 6 scans with 7 sec TR Question: Is there a change in the BOLD response between listening and rest? Stimulus function One session A very simple fMRI experiment

4. stimulus function 1.Decompose data into effects and error 2.Form statistic using estimates of effects and error Make inferences about effects of interestWhy? How? data linear model effects estimate error estimate statistic Modelling the measured data

5. Time BOLD signal Time single voxel time series single voxel time series Voxel-wise time series analysis model specification model specification parameter estimation parameter estimation hypothesis statistic SPM

6. BOLD signal Time =  1 22 + + error x1x1 x2x2 e Single voxel regression model

7. Mass-univariate analysis: voxel-wise GLM = + y y X X Model is specified by 1.Design matrix X 2.Assumptions about e Model is specified by 1.Design matrix X 2.Assumptions about e N: number of scans p: number of regressors N: number of scans p: number of regressors The design matrix embodies all available knowledge about experimentally controlled factors and potential confounds.

8. GLM assumes Gaussian “spherical” (i.i.d.) errors sphericity = i.i.d. error covariance is scalar multiple of identity matrix: Cov(e) =  2 I sphericity = i.i.d. error covariance is scalar multiple of identity matrix: Cov(e) =  2 I Examples for non-sphericity: non-identity non-independence

9. Parameter estimation = + Ordinary least squares estimation (OLS) (assuming i.i.d. error): Objective: estimate parameters to minimize y X

10. y e Design space defined by X x1x1 x2x2 A geometric perspective on the GLM Residual forming matrix R Projection matrix P OLS estimates

11. Deriving the OLS equation OLS estimate

12. x1x1 x2x2 x2*x2* y Correlated and orthogonal regressors When x 2 is orthogonalized with regard to x 1, only the parameter estimate for x 1 changes, not that for x 2 ! Correlated regressors = explained variance is shared between regressors

13. What are the problems of this model? 1.BOLD responses have a delayed and dispersed form. HRF 2.The BOLD signal includes substantial amounts of low- frequency noise. 3.The data are serially correlated (temporally autocorrelated)  this violates the assumptions of the noise model in the GLM

14. The response of a linear time-invariant (LTI) system is the convolution of the input with the system's response to an impulse (delta function). Problem 1: Shape of BOLD response Solution: Convolution model hemodynamic response function (HRF) expected BOLD response = input function  impulse response function (HRF)

15. 1.Express each function in terms of a dummy variable τ. 2.Reflect one of the functions: g( τ )→g( − τ ). 3.Add a time-offset, t, which allows g(t − τ ) to slide along the τ -axis. 4.Start t at -∞ and slide it all the way to +∞. Wherever the two functions intersect, find the integral of their product. In other words, compute a sliding, weighted-average of function f( τ ), where the weighting function is g( − τ ). The resulting waveform (not shown here) is the convolution of functions f and g. If f(t) is a unit impulse, the result of this process is simply g(t), which is therefore called the impulse response. Convolution step-by-step (from Wikipedia):

16. Convolution model of the BOLD response Convolve stimulus function with a canonical hemodynamic response function (HRF):  HRF

17. Problem 2: Low-frequency noise Solution: High pass filtering discrete cosine transform (DCT) set S = residual forming matrix of DCT set

18. High pass filtering: example blue = data black = mean + low-frequency drift green = predicted response, taking into account low-frequency drift red = predicted response, NOT taking into account low-frequency drift

19. with 1 st order autoregressive process: AR(1) autocovariance function Problem 3: Serial correlations

20. Dealing with serial correlations Pre-colouring: impose some known autocorrelation structure on the data (filtering with matrix W ) and use Satterthwaite correction for df’s. Pre-whitening: 1. Use an enhanced noise model with multiple error covariance components, i.e. e ~ N(0,  2 V) instead of e ~ N(0,  2 I). 2. Use estimated serial correlation to specify filter matrix W for whitening the data.

21. How do we define W ? Enhanced noise model Remember linear transform for Gaussians Choose W such that error covariance becomes spherical Conclusion: W is a simple function of V  so how do we estimate V ?

22. Estimating V : Multiple covariance components = 1 + 2 Q1Q1 Q2Q2 Estimation of hyperparameters with ReML (restricted maximum likelihood). V enhanced noise model error covariance components Q and hyperparameters 

23. Contrasts & statistical parametric maps Q: activation during listening ? c = 1 0 0 0 0 0 0 0 0 0 0 Null hypothesis:

24. c = 1 0 0 0 0 0 0 0 0 0 0 ReML- estimates t-statistic based on ML estimates For brevity:

25. head movements arterial pulsations (particularly bad in brain stem) breathing eye blinks (visual cortex) adaptation affects, fatigue, fluctuations in concentration, etc. Physiological confounds

26. Outlook: further challenges correction for multiple comparisons variability in the HRF across voxels slice timing limitations of frequentist statistics  Bayesian analyses GLM ignores interactions among voxels  models of effective connectivity These issues are discussed in future lectures.

27. Correction for multiple comparisons Mass-univariate approach: We apply the GLM to each of a huge number of voxels (usually > 100,000). Threshold of p<0.05  more than 5000 voxels significant by chance! Massive problem with multiple comparisons! Solution: Gaussian random field theory

28. Variability in the HRF HRF varies substantially across voxels and subjects For example, latency can differ by ± 1 second Solution: use multiple basis functions See talk on event-related fMRI

29. Summary Mass-univariate approach: same GLM for each voxel GLM includes all known experimental effects and confounds Convolution with a canonical HRF High-pass filtering to account for low-frequency drifts Estimation of multiple variance components (e.g. to account for serial correlations)

30. Bibliography Friston, Ashburner, Kiebel, Nichols, Penny (2007) Statistical Parametric Mapping: The Analysis of Functional Brain Images. Elsevier. Christensen R (1996) Plane Answers to Complex Questions: The Theory of Linear Models. Springer. Friston KJ et al. (1995) Statistical parametric maps in functional imaging: a general linear approach. Human Brain Mapping 2: 189-210.